1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to novel aryl substituted pyridines and the discovery that these compounds act as blockers of sodium (Na+) channels.
2. Related Art
Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity (Catterall, W. A., Trends Pharmacol. Sci. 8:57–65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na+ ions.
Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp Ther 269:854–859 (1994); Brown et al., British J. Pharmacol. 115:1425–1432 (1995)).
The neuroprotective activity of Na+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na+ channel blockers prevent hypoxic damage to mammalian white matter (Stys el al., J. Neurosci. 12:430–439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
Another example of clinical use of a Na+ channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330:585–591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309–316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55: 70–76 (1994)). Furthermore, based on a number of similiarities between chronic pain and tinnitus, (Moller, A. R. Am. J. Otol. 18: 577–585 (1997); Tonndorf, J. Hear. Res. 28: 271–275 (1987)) it has been proposed that tinnitus should be viewed as a form of chronic pain sensation (Simpson, J. J. and Davies, E. W. Tip. 20: 12–18 (1999)). Indeed, lignocaine and carbamazepine have been shown to be efficacious in treating tinnitus (Majumdar, B. el al. Clin. Otolaryngol. 8: 175–180 (1983); Donaldson, I. Laryngol. Otol. 95: 947–951 (1981)).
It has been established that there are at least five to six sites on the voltage-sensitive Na+ channels which bind neurotoxins specifically (Catterall, W. A., Science 242:50–61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na+ channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15–43 (1980)).
JP 07076542 A2 describes liquid crystals and liquid crystal compositions comprising the following compounds:

U.S. Pat. No. 5,403,934 describes the following intermediates for preparing antimalarials:

Liao et al. (J. Heterocycl. Chem. 13:1283–1288 (1976)) describe the following formula:

Salman (Pharmazie 54:178–183 (1999)) describes an antibacterial/antifungal compound of formula:
wherein Y is NHMe or OMe.
WO 9938829 describes a compound of formula:
This compound is described to be useful as an immunosuppressant or an antiallegy agent.
Karamysheva et al. (Mol. Cryst. Liq. Cryst. 67:241–251 (1981)) describe compounds of formula:
wherein Y is a straight chain C4–C8 alkyl or alkoxy.
DE 3245950 describes a compound of the following formula that is described to be useful as an antihypertensive:

U.S. Pat. No. 4,920,119 describes several 2-phenyl-3-aminopyridine-4-carboxamide derivatives as reactants.
Troschuetz et al. (Chem.-Ztg. 114:321–322 (1990)) describe a compound of formula:

Goerlitzer et al (Arch. Pharm. (Weinheim, Ger.) 325:357–359 (1992)) describe a compound of formula:

U.S. Pat. No. 5,389,632 describes the following compounds as reactants:

Goerlitzer et al (Pharmazie 52:97–100 (1997)) describe the following compounds:
where Y is OMe or OEt.
Chambers et al. (Bioorg. Med. Chem. Lett. 7:739–744 (1997)) describe the following compounds as useful in the treatment of rheumatoid arthritis:

Reddy et al (Synth. Commun. 27:2217–2222 (1997)) describe the following formula:
where Y is H or CF3.
Rottlander et al. (Synlett (9):1084–1086 (1997)) describe 3-(4-methoxyphenyl)pyridine-4-carboxamide.
Singh et al. (Indian J. Chem., Sect. B. Org. Chem. Incl. Med. Chem. 37B(5):517–520 (1998)) describe 2-amino-4-n-butoxy-5-(4-methoxyphenyl)pyridine-3-carboxamide.